Michigan Hepatotoxicity Research Network 2018 Renewal ABSTRACT In the past 5 years, the Drug Induced Liver Injury Network (DILIN) has increased cumulative enrollment to over 2000 adult and pediatric patients in the ongoing Prospective and Retrospective registry studies. In addition, an ?Acute? DILI protocol with collection of serial early biological samples for mechanistic biomarker studies was developed and implemented. Other network aims included investigation of the role of genetic polymorphisms in DILI susceptibility and outcome, development of improved causality assessment methods, and expansion of the LiverTox website. The University of Michigan team led by Dr. Fontana has played an important role in the design, implementation, and analysis of the primary and ancillary DILIN studies since its inception in 2003. Michigan has not only been a leading enroller in all of the ongoing Registry studies but also provided important leadership in multiple DILIN committees and initiatives. The Michigan team now proposes a series of novel and feasible study aims for the DILIN renewal. The PRIMARY AIM of this proposal is to continue to recruit and enroll high causality adult and pediatric DILI cases into the registry studies for genetic, immunologic, biomarker and mechanistic studies. The Michigan Hepatotoxicity Network has specific plans to increase the enrollment of ethnic minorities via the engagement of hepatologists/ collaborators in southeastern Michigan and elsewhere that care for a large number of African American, Hispanic, and Asian patients. In addition, further development of natural language processing algorithms to search the EMR at the University of Michigan are proposed to facilitate enrollment. Qualitative, quantitative and toxicological studies of the chemical constituents in the herbal and dietary supplement (HDS) products implicated in a growing proportion of DILI cases will be expanded via an ongoing collaboration with the National Center for National Products Research. The SECOND AIM of this proposal is to conduct pilot/ feasibility clinical trials to improve the outcomes of patients with severe acute DILI and those at risk for developing chronic DILI. Proposed study designs include a 12 week course of a simple and safe, orally administered anti-inflammatory or anti-oxidant agent (e.g. budesonide, SAMe, vitamin E) in selected patients with severe acute DILI at risk for adverse outcomes. In addition, 12 to 24 week studies of a safe and effective orally administered anti- cholestatic agent such as an ileal apical bile salt transport inhibitor that may reduce serum bile acids are proposed for subjects at risk of chronic DILI. Lastly, prospective studies of magnetic resonance elastography and MRCP imaging are proposed to improve our understanding of the severity and natural history of DILI. The THIRD AIM of this proposal is to further expand the LiverTox website to include additional chapters on HDS DILI, develop and implement a computerized causality assessment instrument, and assemble working committees to insure that the website content remains up to date and pertinent. Finally, additional collaborations between DILIN and the US FDA and other regulatory agencies are proposed to enhance the pharmacovigilance capabilities of DILIN for new causes of DILI and temporal changes over time.